PROJECT SUMMARY Environmental degradation and exposure to heavy metals (over which individuals often have little control) may have a direct impact on cardiovascular diseases (CVD) development, which have become one of the most pressing nemesis for individual- and population-health globally. Recent studies have provided provocative evidence linking environmental exposure to heavy metals to increased risk of diabetes and hypertension, which are strong CVD risk factors. In contrast, prospective cohort studies have shown that higher levels of dietary and serum essential trace metals are directly associated with lower CVD risk and that supplementation of which may have potential benefits by mitigating the effects of toxic metals on the cardiovascular system. However, very few studies have directly and comprehensively investigated exposure to multiple metals particularly their joint effects on affecting CVD risk (including stroke). The ongoing Brazilian Longitudinal Study of Adult Health (in Portuguese, ?Estudo Longitudinal de Sau de do Adulto?, ELSA-Brasil), the only large prospective study established in South America to specifically investigate risk factors for cardiometabolic health, represents a unique resource to study the roles of multiple metal exposures and their interactions with dietary trace elements in affecting CVD risk. At baseline, 4,428 CVD-free participants at the ELSA-Brasil site in Sao Paulo completed 1) physical examinations; 2) clinical laboratory tests; 3) in-person interviews; 4) collections of blood and urine samples; and 5) a CT examination to quantify coronary artery calcium (CAC) score. To date, a total of 466 incident CVD (~150 stroke) cases have been adjudicated in the ELSA-Brasil cohort in the 10-year follow up. ln the current application aims to investigate, we will leverage these exceptional resources and the substantial investment of time and effort by ELSA-Brasil study investigators over the past ten years to investigate, in a most cost-efficient and timely manner, the roles of metals playing in CVD development. Specifically, the current application aims to utilize this ongoing prospective cohort study to not only determine whether heavy metal exposures increase CAC score and CVD risk, but also identify the optimal body levels of essential metals that could mitigate CVD risk from toxic metals. If antagonistic effects exist and optimal body levels of essential metals that could reduce toxic metal impacts are confirmed, this work would lead to simple, safe, readily-available, acceptable and highly-affordable nutritional intervention for CVD prevention that will have both clinical and public health significance worldwide.